For decades, fluorouracil (FU) was the sole active agent. This has changed markedly since the year 2000, with the approval of irinotecan, oxaliplatin, three humanized monoclonal antibodies (MoAbs) that target the vascular endothelial growth factor (VEGF; bevacizumab) and epidermal growth factor receptor (EGFR; cetuximab and panitumumab), intravenous aflibercept, a recombinant fusion protein consisting of VEGF binding portions from the human VEGF receptors 1 and 2 fused to the Fc portion of human immunoglobulin G1, regorafenib, an orally active inhibitor of angiogenic tyrosine kinases (including the VEGF receptors 1, 2, and 3) as well as several other membrane-bound and intracellular kinases that are involved in normal cellular function and in pathologic processes, and trifluridine-tipiracil (TAS-102), an oral cytotoxic agent that consists of the nucleoside analog trifluridine (a cytotoxic antimetabolite that inhibits thymidylate synthetase and, after modification within tumor cells, is incorporated into DNA causing strand breaks) and tipiracil, a potent thymidine phosphorylase inhibitor, which inhibits trifluridine metabolism and has antiangiogenic properties as well. The best way to combine and sequence these agents is still not established.

The best way to combine and sequence all of these agents is not known. Increasingly, biomarker expression is driving therapeutic decision-making. However, the biologic targets for most of the agents that are active against mCRC are unknown, with the exception of agents targeting the EGFR. Benefit from monoclonal antibodies targeting the EGFR is restricted to patients whose tumors do not contain mutated RAS genes. Furthermore, response to EGFR-targeted agents is highly unlikely in patients whose tumors harbor BRAF mutations (particularly the BRAF V600E mutation).

Until the development of combination regimens of leucovorin (LV)-modulated fluorouracil (FU) with either irinotecan or oxaliplatin, FU/LV was the standard first-line therapy for metastatic colorectal cancer (mCRC), and it is still used in patients who cannot tolerate these triple-drug regimens. If it is to be used alone, because of the more favorable toxicity profile, we recommend short-duration infusional FU/LV (ie, the de Gramont regimen) [1] rather than the Mayo regimen of treatment for five consecutive days once per month. An acceptable alternative is weekly FU (500 mg/m2) plus LV (500 mg/m2) for six of every eight weeks [2].

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